Mechanistic Conundrum of C–C Bond Cleavage by CYP51

Abstract

Cytochrome P45051 (CYP51) catalyzes C–C bond cleavage during the biosynthesis of the sterol, using a mechanism which is still under debate. Moreover, the mechanistic conundrum is aggravated by the experimental results, which show that the C–C bond cleavage reaction step may start either from the gem-diol or aldehyde intermediates. The present study uses hybrid QM/MM calculations (exploration of potential energy surface) supplemented by long-scale MD simulations to elucidate the mechanism of C–C bond cleavage in 14α-demethylation of lanosterol using both gem-diol and aldehyde as starting substrates for the reaction. For gem-diol, the reaction proceeds via a proton-coupled electron transfer (PCET) type pathway. However, in the aldehyde form, demethylation follows a surprising mechanism assisted by a water molecule. In both mechanisms, the active catalyst is the classical Compound I species, [(Por+•)(Scys)FeIVO]. Since the C–C cleavage plays a crucial role in the natural biosynthesis of many complex organic molecules in the biological kingdom, the present study provides a testable mechanism of this enigmatic reaction.